US7381722B2 - Tetracyclic amino and carboxamido compounds and methods of use thereof - Google Patents

Tetracyclic amino and carboxamido compounds and methods of use thereof Download PDF

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US7381722B2
US7381722B2 US11/354,707 US35470706A US7381722B2 US 7381722 B2 US7381722 B2 US 7381722B2 US 35470706 A US35470706 A US 35470706A US 7381722 B2 US7381722 B2 US 7381722B2
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tetracyclic
halo
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Prakash Jagtap
Csaba Szabo
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Rocket Pharmaceuticals Inc
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Inotek Pharmaceuticals Corp
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Definitions

  • the present invention relates to Tetracyclic Amino Compounds and Tetracyclic Carboxamido Compounds, compositions comprising an effective amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and methods for treating or preventing an inflammatory disease, a reperfusion injury, diabetes, a diabetic complication, reoxygenation injury resulting from organ transplantation, an ischemic condition, Parkinson's disease, renal failure, a vascular disease, a cardiovascular disease, or cancer, comprising administering to a subject in need thereof an effective amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound.
  • Inflammatory diseases such as arthritis, colitis, and autoimmune diabetes
  • inflammatory disease and reperfusion injury can induce proinflammatory cytokine and chemokine synthesis which can, in turn, result in production of cytotoxic free radicals such as nitric oxide and superoxide. NO and superoxide can react to form peroxynitrite (ONOO ⁇ ) (Szabó et al., Shock 6:79-88, 1996).
  • the ONOO ⁇ -induced cell necrosis observed in inflammatory disease and in reperfusion injury involves the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS).
  • PARS nuclear enzyme poly synthetase
  • Activation of PARS is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion injury (Szabó et al., Trends Pharmacol. Sci. 19:287-98, 1998).
  • Isoquinoline compounds have been previously discussed in the art. For example, cytotoxic non-camptothecin topoisomerase I inhibitors are reported in Cushman et al., J. Med. Chem., 43:3688-3698, 2300 and Cushman et al., J. Med. Chem. 42:446-57, 1999; indeno[1,2-c]isoquinolines are reported as antineoplastic agents in Cushman et al., WO 00/21537; and as neoplasm inhibitors in Hrbata et al., WO 93/05023.
  • the invention provides a compound of Formula (I)
  • R 1 , R 2 , R 3 and R 4 groups is —NH(CH 2 ) n —-N(R 5 )(R 6 ) and the remaining groups are simultaneously —H;
  • R 5 and R 6 are independently —H, —C 1 -C 6 alkyl, -phenyl, or benzyl, wherein the —C 1 -C 6 alkyl, -phenyl, or benzyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently —H or —C 1 -C 5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3 and Z 4 are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5 alkyl, -halo, -halo-substituted C 1 -C 5 alkyl, hydroxy, —O—C 1 -C 5 alkyl,
  • n is an integer ranging from 2 to 6.
  • the invention includes a compound of Formula (II)
  • R 1 , R 2 , R 3 and R 4 groups is —C(O)NH(CH 2 ) n —N(R 5 )(R 6 ) and the remaining groups are simultaneously —H;
  • R 5 and R 6 are independently —H, —C 1 -C 6 alkyl, -phenyl, or benzyl, wherein the —C 1 -C 6 alkyl, -phenyl, or benzyl, is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently —H or —C 1 -C 5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3 and Z 4 are taken together to form an nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5 alkyl, -halo, -halo-substituted C 1 -C 5 alkyl, hydroxy, —O—C 1 -C 5 alkyl,
  • n is an integer ranging from 2 to 6.
  • a Compound of Formula (I) or a pharmaceutically acceptable salt thereof (a “Tetracyclic Amino Compound”) and a compound of Formula (II) or a pharmaceutically acceptable salt thereof (a “Tetracyclic Carboxamido Compound”) are useful for treating or preventing an inflammatory disease, a reperfusion injury, diabetes, a diabetic complication, reoxygenation injury resulting from organ transplantation, an ischemic condition, Parkinson's disease, renal failure, a vascular disease, a cardiovascular disease, or cancer (each being a “Condition”).
  • Also provided by the invention are methods for treating or preventing a Condition, comprising administering to a subject in need of such treatment or prevention an effective amount of a Tetracyclic Amino Compound.
  • the invention further provides compositions comprising and an effective amount of a Tetracyclic Amino Compound and a physiologically acceptable carrier or vehicle.
  • Also provided by the invention are methods for treating or preventing a Condition, comprising administering to a subject in need of such treatment or prevention an effective amount of a Tetracyclic Carboxamido Compound.
  • compositions comprising and an effective amount of a Tetracyclic Carboxamido Compound and a physiologically acceptable carrier or vehicle.
  • —C 1 -C 5 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 5 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative straight chain —C 1 -C 5 alkyls include -methyl, -ethyl, -n-propyl, -n-butyl and -n-pentyl.
  • Representative branched —C 1 -C 5 alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl and 1,2-dimethylpropyl.
  • —C 1 -C 6 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative straight chain —C 1 -C 6 alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl.
  • Representative branched —C 1 -C 6 alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, -1-methylbutyl, -isohexyl, -neohexyl, -2-methylbutyl, -3-methylbutyl, -1,1-dimethylpropyl and -1,2-dimethylpropyl.
  • —C 1 -C 10 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, wherein one of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative —C 1 -C 10 alkyls include, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -nonyl, decyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, isononyl and isodecyl.
  • —C 1 -C 5 alkylene- refers to a straight chain or branched acylic hydrocarbon having from 1-5 carbon atoms, wherein two of the hydrocarbon's hydrogen atoms has been replaced by a single bond.
  • Representative —C 1 -C 5 alkylene-groups include methylene, ethylene, propylene, butylene, and pentylene.
  • —C 1 -C 5 alkylene-groups include —CH(CH 3 )—, —CH 2 CH(CH 3 )—, —CH 2 CH 2 CH(CH 3 )—, —CH 2 CH(CH 3 )CH 2 —, —CH(CH 3 )CH(CH 3 )—, —CH 2 CH 2 CH 2 CH(CH 3 )—, —CH 2 CH 2 CH(CH 3 )CH 2 —, —CH(CH 3 )CH(CH 3 )CH 2 — and —CH(CH 3 )CH 2 CH(CH 3 )—.
  • a “nitrogen containing 3- to 7-membered monocyclic heterocycle” refers to a monocyclic 3- to 7-membered aromatic or non-aromatic monocyclic cycloalkyl group in which one of the cycloalkyl group's ring carbon atoms has been replaced with a nitrogen atom and 0-4 of the cycloalkyl group's remaining ring carbon atoms may be independently replaced with a N, O or S atom.
  • the nitrogen containing 3- to 7-membered monocyclic heterocycles can be attached via a nitrogen, sulfur, or carbon atom.
  • nitrogen-containing-3- to 7-membered monocyclic heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrimidinyl, and morpholinyl.
  • a nitrogen containing 3- to 7-membered monocyclic heterocycle is substituted with up to three groups, independently chosen from: —C 1 -C 5 alkyl, -halo, -halo-substituted C 1 -C 5 alkyl, hydroxy, —O—C 1 -C 5 alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5 alkyl), —OC(O)—(C 1 -C 5 alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a is independently —H, -benzyl, or —C 1 -C 10 alkyl.
  • Halo is —F, —Cl, —Br or —I.
  • a “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. In one embodiment, the subject is a human.
  • salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorsulfonate, camsylate, carbonate, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate
  • the pharmaceutically acceptable salt is a mesylate salt.
  • the pharmaceutically acceptable salt is a camphorsulfonate salt.
  • an “effective amount” when used in connection with a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound is an amount that is effective for treating or preventing a Condition.
  • an “effective amount” when used in connection with another anticancer agent is an amount that is effective for treating or preventing cancer alone or in combination with a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound. “In combination with” includes administration within the same composition and within separate compositions. In the latter instance, the anticancer agent is administered during a time when the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound exerts its prophylactic or therapeutic effect, or vice versa.
  • the present invention provides Tetracyclic Amino Compounds according to Formula (I), below:
  • R 1 , R 2 , R 3 and R 4 are as defined above for the compounds of formula (I).
  • R 1 is —NH(CH 2 ) n —N(R 5 )(R 6 ) and R 2 , R 3 and R 4 are each hydrogen.
  • R 2 is —NH(CH 2 ) n —N(R 5 )(R 6 ) and R 1 , R 3 and R 4 are each hydrogen.
  • R 3 is —NH(CH 2 ) n —N(R 5 )(R 6 ) and R 1 , R 2 and R 4 are each hydrogen.
  • R 4 is —NH(CH 2 ) n —N(R 5 )(R 6 ) and R 1 , R 2 and R 3 are each hydrogen.
  • n is 2.
  • n 3.
  • n 4.
  • n is 5.
  • n 6
  • R 5 and R 6 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5 alkyl, -halo, -halo-substituted C 1 -C 5 alkyl, hydroxy, —O—C 1 -C 5 alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5 alkyl), —OC(O)—(C 1 -C 5 alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a is independently —H, -benzyl, or —C 1 -C 10 alkyl.
  • —N(R 5 )(R 6 ) is:
  • Tetracyclic Amino Compounds of Formula (I) include the compounds of Formula (Ia) as set forth below:
  • Tetracyclic Amino Compounds of Formula (I) include the compounds of Formula (Ib) as set forth below:
  • Tetracyclic Amino Compounds of Formula (I) include the compounds of Formula (Ic) as set forth below:
  • Tetracyclic Amino Compounds of Formula (I) include the compounds of Formula (Id) as set forth below:
  • the present invention provides Tetracyclic Carboxamido Compounds according to Formula (II), below:
  • R 1 , R 2 , R 3 and R 4 are as defined above for the compounds of formula (II).
  • R 1 is —C(O)NH—(CH 2 ) n —N(R 5 )(R 6 ) and R 2 , R 3 and R 4 are each hydrogen.
  • R 2 is —C(O)NH—(CH 2 ) n —N(R 5 )(R 6 ) and R 1 , R 3 and R 4 are each hydrogen.
  • R 3 is —C(O)NH—(CH 2 ) n —N(R 5 )(R 6 ) and R 1 , R 2 and R 4 are each hydrogen.
  • R 4 is —C(O)NH—(CH 2 ) n —N(R 5 )(R 6 ) and R 1 , R 2 and R 3 are each hydrogen.
  • n is 2.
  • n 3.
  • n 4.
  • n is 5.
  • R 5 and R 6 are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one to three of —C 1 -C 5 alkyl, -halo, -halo-substituted C 1 -C 5 alkyl, hydroxy, —O—C 1 -C 5 alkyl, —N(R a ) 2 , —COOH, —C(O)O—(C 1 -C 5 alkyl), —OC(O)—(C 1 -C 5 alkyl), —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a is independently —H, -benzyl, or —C 1 -C 10 alkyl.
  • —N(R 5 )(R 6 ) is:
  • Tetracyclic Carboxamido Compounds of Formula (II) include the compounds of Formula (IIa) as set forth below:
  • Tetracyclic Carboxamido Compounds of Formula (II) include the compounds of Formula (IIb) as set forth below:
  • Tetracyclic Carboxamido Compounds of Formula (II) include the compounds of Formula (IIc) as set forth below:
  • Tetracyclic Carboxamido Compounds of Formula (II) include the compounds of Formula (IId) as set forth below:
  • each X is independently —Cl or —Br, and n, R 5 and R 6 are defined above for the Compounds of Formula (I).
  • Homophthalic anhydride 1 can be coupled with a nitrobenzene compound of formula 2 in the presence of a base, for example, an amine base, to provide a tetracyclic nitro intermediate of formula 3.
  • the nitro group of 3 can be reduced using, for example, catalytic hydrogenation with a platinum or palladium catalyst, to provide an amino compound of formula 4.
  • a compound of formula 4 can then be reacted with a stoichometric excess of an acid halide compound of formula 5 to provide an amido compound of formula 6.
  • the chlorine or bromine atom of 6 can then be displaced by an amine of formula NH(R 5 )(R 6 ) to provide an amino compound of formula 7.
  • the amide moiety of a compound of formula 7 can be reduced using lithium aluminum hydride to provide the Tetracyclic Amino Compounds of Formula (I).
  • R is methyl or ethyl
  • n, R 5 and R 6 are defined above for the Compounds of Formula (II).
  • Homophthalic anhydride 1 can be coupled with a phenylester compound of formula 2 in the presence of a base, for example, an amine base, to provide a tetracyclic nitro intermediate of formula 3.
  • the ester group of 3 can be hydrolyzed under basic or acidic conditions to provide an carboxylic acid compound of formula 4.
  • a compound of formula 3 or formul 4 can then be coupled with a diaminoalkyl compound of formula 5 (which is commercially available, or can be prepared by reacting dihaloalkyl compounds with various amines using methods well known to one of skill in the art of organic synthesis) to provide the Tetracyclic Carboxamido Compounds of Formula (II).
  • n, R 5 and R 6 are defined as above for compounds of formula (IId).
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds are administered to a subject in need of treatment or prevention of a Condition.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be used to treat an inflammatory disease.
  • Inflammatory diseases can arise where there is an inflammation of the body tissue. These include local inflammatory responses and systemic inflammation.
  • Examples of inflammatory diseases treatable or preventable using the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds include, but are not limited to, organ transplant rejection; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum
  • the inflammatory disease can also be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
  • shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.
  • the inflammatory disease is the inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, an inflammatory disease of the eye, gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock or chemotherapeutic shock.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be used to treat a reperfusion injury.
  • Reperfusion refers to the process whereby blood flow in the blood vessels is resumed following ischemia, such as occurs following constriction or obstruction of the vessel.
  • Reperfusion injury can result following a naturally occurring episode, such as a myocardial infarction, stroke, or during a surgical procedure where blood flow in vessels is intentionally or unintentionally blocked.
  • Examples of reperfusion injuries treatable or preventable using the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds include, but are not limited to, intestinal reperfusion injury, myocardial reperfusion injury, and reperfusion injury resulting from cardiopulmonary bypass surgery, aortic aneurysm repair surgery, carotid endarterectomy surgery, or hemorrhagic shock.
  • the reperfusion injury results from cardiopulmonary bypass surgery, aortic aneurysm repair surgery, carotid endarterectomy surgery or hemorrhagic shock.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be used to treat or prevent reoxygenation injury resulting from organ transplantation.
  • reoxygenation injuries treatable or preventable using the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds include, but are not limited to, transplantation of the following organs: heart, lung, liver, kidney, pancreas, intestine and cornea.
  • reoxygenation injury resulting from organ transplantation occurs during the organ transplantation.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be used to treat or prevent an ischemic condition.
  • ischemic conditions treatable or preventable using the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds include, but are not limited to, stable angina, unstable angina, myocardial ischemia, hepatic ischemia, mesenteric artery ischemia, ischemic heart disease, intestinal ischemia, critical limb ischemia, chronic critical limb ischemia, cerebral ischemia, acute cardiac ischemia, and an ischemic disease of the central nervous system, such as stroke or cerebral ischemia.
  • the ischemic condition is myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease or cerebral ischemia.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be used to treat or prevent renal failure.
  • the renal failure is chronic renal failure.
  • the renal failure is acute renal failure.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be used to treat or prevent a vascular disease other than a cardiovascular disease.
  • vascular diseases treatable or preventable using the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds include, but are not limited to, peripheral arterial occlusion, thromboangitis obliterans, Reynaud's disease and phenomenon, acrocyanosis, erythromelalgia, venous thrombosis, varicose veins, arteriovenous fistula, lymphedema, and lipedema.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be used to treat or prevent a cardiovascular disease.
  • cardiovascular diseases treatable or preventable using the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds include, but are not limited to, chronic heart failure, atherosclerosis, congestive heart failure, hypercholesterolemia, circulatory shock, cardiomyopathy, cardiac transplant, myocardial infarction, and a cardiac arrhythmia, such as atrial fibrillation, supraventricular tachycardia, atrial flutter, and paroxysmal atrial tachycardia.
  • the cardiovascular disease is chronic heart failure.
  • the cardiovascular disease is a cardiac arrhythmia.
  • the cardiac arrhythmia is atrial fibrillation, supraventricular tachycardia, atrial flutter or paroxysmal atrial tachycardia.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be used to treat or prevent diabetes mellitus or its complications.
  • diabetes mellitus that are treatable or preventable using the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds include, but are not limited to, Type I diabetes (Insulin Dependent Diabetes Mellitus), Type II diabetes (Non-Insulin Dependent Diabetes Mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), Type A insulin resistance syndrome, Type B insulin resistance syndrome, lipatrophic diabetes, and diabetes induced by ⁇ -cell toxins.
  • Type I diabetes Insulin Dependent Diabetes Mellitus
  • Type II diabetes Non-In
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can also be used to treat or prevent a complication of diabetes mellitus.
  • complications of diabetes mellitus that are treatable or preventable using the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds include, but are not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy, (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, gangrene of the feet, immune-complex vasculitis, systemic lupus erythematosus (SLE), atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, mononeuropathies, autonomic neuropathy, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candid
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be used to treat or prevent Parkinson's disease.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be used to treat or prevent cancer.
  • the invention provides methods for treating or preventing cancer, comprising administering to a subject in need of such treatment or prevention: (i) an effective amount of a Tetracyclic Amino Compound; and (ii) an effective amount of another anticancer agent.
  • the invention further provides methods for treating or preventing cancer, comprising administering to a subject in need of such treatment or prevention: (i) an effective amount of a Tetracyclic Carboxamido Compound; and (ii) an effective amount of the other anticancer agent.
  • Examples of cancers treatable or preventable using the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds include, but are not limited to, the cancers disclosed below in Table 1 and metastases thereof.
  • Solid tumors including but not limited to: fibrosarcoma myxosarcoma liposarcoma chondrosarcoma osteogenic sarcoma chordoma angiosarcoma endotheliosarcoma lymphangiosarcoma lymphangioendotheliosarcoma synovioma mesothelioma Ewing's tumor leiomyosarcoma rhabdomyosarcoma colon cancer colorectal cancer kidney cancer pancreatic cancer bone cancer breast cancer ovarian cancer prostate cancer esophageal cancer stomach cancer oral cancer nasal cancer throat cancer squamous cell carcinoma basal cell carcinoma adenocarcinoma sweat gland carcinoma sebaceous gland carcinoma papillary carcinoma papillary adenocarcinomas cystadenocarcinoma medullary carcinoma bronchogenic carcinoma renal cell carcinoma hepatoma bile duct carcinoma choriocarcinoma seminoma embryonal carcinoma Wilms' tumor cervical cancer uter
  • the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, non-Hodgkin's lymphoma, skin cancer, a brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer.
  • the cancer is metastatic cancer.
  • the subject in need of treatment has previously undergone or is presently undergoing treatment for cancer.
  • the treatment includes, but is not limited to, prior chemotherapy, radiation therapy, surgery or immunotherapy, such as administration of cancer vaccines.
  • the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compounds are also useful for the treatment or prevention of a cancer caused by a virus.
  • viruses include human papilloma virus, which can lead to cervical cancer (see, e.g., Hemandez-Avila et al., Archives of Medical Research (1997) 28:265-271); Epstein-Barr virus (EBV), which can lead to lymphoma (see, e.g., Herrmann et al., J Pathol (2003) 199(2):140-5); hepatitis B or C virus, which can lead to liver carcinoma (see, e.g., El-Serag, J Clin Gastroenterol (2002) 35(5 Suppl 2):S72-8); human T cell leukemia virus (HTLV)-I, which can lead to T-cell leukemia (see e.g., Mortreux et al., Leukemia (2003) 17(1):26-38); human herpesvirus-8 infection
  • Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can also be administered to prevent the progression of a cancer, including but not limited to the cancers listed in Table 1.
  • Such prophylactic use includes that in which non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred.
  • the presence of one or more characteristics of a transformed phenotype, or of a malignant phenotype, displayed in vivo or displayed in vitro by a cell sample from a subject can indicate the desirability of prophylactic or therapeutic administration of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound.
  • characteristics of a transformed phenotype include morphology changes, looser substratum attachment, loss of contact inhibition, loss of anchorage dependence, protease release, increased sugar transport, decreased serum requirement, expression of fetal antigens, disappearance of the 250,000 dalton cell surface protein, etc. (see also id., at pp. 84-90 for characteristics associated with a transformed or malignant phenotype).
  • leukoplakia a benign-appearing hyperplastic or dysplastic lesion of the epithelium, or Bowen's disease, a carcinoma in situ, are treatable or preventable according to the present methods.
  • fibrocystic disease cystic hyperplasia, mammary dysplasia, particularly adenosis (benign epithelial hyperplasia) are treatable or preventable according to the present methods.
  • a subject that has one or more of the following predisposing factors for malignancy can be treated by administration of an effective amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound: a chromosomal translocation associated with a malignancy (e.g., the Philadelphia chromosome for chronic myelogenous leukemia; t(14;18) for follicular lymphoma); familial polyposis or Gardner's syndrome; benign monoclonal gammopathy; a first degree kinship with persons having a cancer or precancerous disease showing a Mendelian (genetic) inheritance pattern (e.g., familial polyposis of the colon, Gardner's syndrome, hereditary exostosis, polyendocrine adenomatosis, medullary thyroid carcinoma with amyloid production and pheochromocytoma, Peutz-Jeghers syndrome, neurofibromatosis of Von Recklinghausen,
  • the present methods for treating or preventing cancer can further comprise the administration of another anticancer agent.
  • the present invention provides methods for treating or preventing cancer, comprising the administration of an effective amount of the following to a subject in need thereof: (i) a Tetracyclic Amino Compound and (ii) another anticancer agent.
  • the present invention provides methods for treating or preventing cancer in a subject, the method comprising the administration of an effective amount of the following to a subject in need thereof: (i) a Tetracyclic Carboxamido Compound and (ii) another anticancer agent.
  • Tetracyclic Amino Compound or Tetracyclic Carboxamide Compound and (ii) other anticancer agent can be administered concurrently.
  • the (i) Tetracyclic Amino Compound or Tetracyclic Carboxamide Compound and (ii) other anticancer agent can be administered within the same composition, or can be administered from different compositions, via the same or different routes of administration.
  • the Tetracyclic Amino Compound or Tetracyclic Carboxamide Compound is administered during a time when the other anticancer agent exerts its prophylactic or therapeutic effect, or vice versa.
  • the Tetracyclic Amino Compound or other anticancer agent are administered in doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • the Tetracyclic Carboxamido Compound or other anticancer agent are administered in doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • the Tetracyclic Amino Compound or other anticancer agent are administered in doses that are lower than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • the Tetracyclic Carboxamido Compound or other anticancer agent are administered in doses that are lower than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • the Tetracyclic Amino Compound and other anticancer agent act synergistically and are administered in doses that are lower than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • Tetracyclic Carboxamido Compound and other anticancer agent act synergistically and are administered in doses that are lower than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • the dosage of the Tetracyclic Amino Compound or other anticancer agent administered as well as the dosing schedule can depend on various parameters, including, but not limited to, the cancer being treated, the subject's general health, and the administering physician's discretion.
  • the dosage of the Tetracyclic Carboxamido Compound or other anticancer agent administered as well as the dosing schedule can depend on various parameters, including, but not limited to, the cancer being treated, the subject's general health, and the administering physician's discretion.
  • a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the other anticancer agent, to a subject in need thereof.
  • a (i) Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) the other anticancer agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • a (i) Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) the other anticancer agent are administered within 3 hours. In another embodiment, a (i) Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) the other anticancer agent are administered at 1 minute to 24 hours apart.
  • an effective amount of a Tetracyclic Amino Compound and an effective amount of another anticancer agent are present in the same composition.
  • this composition is useful for oral administration.
  • this composition is useful for intravenous administration.
  • an effective amount of a Tetracyclic Carboxamido Compound and an effective amount of another anticancer agent are present in the same composition.
  • this composition is useful for oral administration.
  • this composition is useful for intravenous administration.
  • Cancers that can be treated or prevented by administering a (i) Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) the other anticancer agent include, but are not limited to, the list of cancers set forth above in Table 1.
  • the cancer is brain cancer.
  • the brain cancer is pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme or a metastatic brain tumor.
  • the cancer is melanoma.
  • the melanoma is metastatic melanoma.
  • the (i) Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound and (ii) other anticancer agent can act additively or synergistically.
  • a synergistic combination of a (i) Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) the other anticancer agent might allow the use of lower dosages of one or both of these agents and/or less frequent administration of the agents to a subject with cancer.
  • the ability to utilize lower dosages of one or both of the (i) Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound and (ii) other anticancer agent and/or to administer the agents less frequently can reduce any toxicity associated with the administration of the agents to a subject without reducing the efficacy of the agents in the treatment of cancer.
  • a synergistic effect might result in the improved efficacy of these agents in the treatment of cancer and/or the reduction of any adverse or unwanted side effects associated with the use of either agent alone.
  • the (i) Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound and (ii) one or more other anticancer agents act synergistically when administered in doses typically employed when such agents are used as monotherapy for the treatment of cancer.
  • the (i) Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound and (ii) one or more other anticancer agents act synergistically when administered in doses that are lower than doses typically employed when such agents are used as monotherapy for the treatment of cancer.
  • the administration of an effective amount of (i) a Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound and (ii) an effective amount of another anticancer agent inhibits the resistance of a cancer to the other anticancer agent.
  • the cancer is a tumor.
  • Suitable other anticancer agents useful in the methods and compositions of the present invention include, but are not limited to temozolomide, a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, taxanes such as docet
  • the other anticancer agent is, but is not limited to, a drug listed in Table 2.
  • additional anticancer agents that can be used in the compositions and methods of the present invention include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin
  • anticancer drugs that can be used in the methods and compositions of the invention include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid
  • the other anticancer agent is interferon- ⁇ .
  • the other anticancer agent is interleukin-2.
  • the other anticancer agent is an alkylating agent, such as a nitrogen mustard, a nitrosourea, an alkylsulfonate, a triazene, or a platinum-containing agent.
  • an alkylating agent such as a nitrogen mustard, a nitrosourea, an alkylsulfonate, a triazene, or a platinum-containing agent.
  • the other anticancer agent is a triazene alkylating agent.
  • the other anticancer agent is temozolomide.
  • Temozolomide can be administered to a subject at dosages ranging from about 60 mg/m 2 (of a subject's body surface area) to about 250 mg/m 2 and from about 100 mg/m 2 to about 200 mg/m 2 .
  • the dosages of temozolomide are about 10 mg/m 2 , about 1 mg/m 2 , about 5 mg/m 2 , about 10 mg/m 2 , about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 , about 200 mg
  • temozolomide is administered orally.
  • temozolomide is administered orally to a subject at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 .
  • temozolomide is administered orally to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 .
  • temozolomide is administered orally to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 on days 1-5, then again orally once per day for five consecutive days on days 28-32 at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 , then again orally once per day for five consecutive days on days 55-59 at a dose ranging from about 150 mg/m 2 to about 200 mg/m 2 .
  • the other anticancer agent is procarbazine.
  • Procarbazine can be administered to a subject at dosages ranging from about 50 mg/m 2 (of a subject's body surface area) to about 100 mg/m 2 and from about 60 mg/m 2 to about 100 mg/m 2 .
  • the dosages of procarbazine are about 10 mg/m 2 , about 1 mg/m 2 , about 5 mg/m 2 , about 10 mg/m 2 , about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 , about 200 mg
  • procarbazine is administered intravenously.
  • procarbazine is administered intravenously to a subject at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 .
  • procarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 .
  • procarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 , then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 .
  • procarbazine is administered once intravenously to a subject at a dose ranging from about 50 mg/m 2 to about 100 mg/m 2 .
  • the other anticancer agent is dacarbazine.
  • dacarbazine can be administered to a subject at dosages ranging from about 60 mg/m 2 (of a subject's body surface area) to about 250 mg/m 2 and from about 150 mg/m 2 to about 250 mg/m 2 .
  • the dosages of dacarbazine are about 10 mg/m 2 , about 1 mg/m 2 , about 5 mg/m 2 , about 10 mg/m 2 , about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 , about
  • dacarbazine is administered intravenously.
  • dacarbazine is administered intravenously to a subject at a dose ranging from about 150 mg/m 2 to about 250 mg/m 2 .
  • dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m 2 to about 250 mg/m 2 .
  • dacarbazine is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 150 mg/m 2 to about 250 mg/m 2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 150 mg/m 2 to about 250 mg/m 2 , then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 150 mg/m 2 to about 250 mg/m 2 .
  • dacarbazine is administered once intravenously to a subject at a dose ranging from about 150 mg/m 2 to about 250 mg/m 2 .
  • the other anticancer agent is a Topoisomerase I inhibitor, such as etoposide, teniposide, topotecan, irinotecan, 9-aminocamptothecin, camptothecin, or crisnatol.
  • Topoisomerase I inhibitor such as etoposide, teniposide, topotecan, irinotecan, 9-aminocamptothecin, camptothecin, or crisnatol.
  • the other anticancer agent is irinotecan.
  • Irinotecan can be administered to a subject at dosages ranging from about 50 mg/m 2 (of a subject's body surface area) to about 150 mg/m 2 and from about 75 mg/m 2 to about 150 mg/m 2 .
  • the dosages of irinotecan are about 10 mg/m 2 , about 1 mg/m 2 , about 5 mg/m 2 , about 10 mg/m 2 , about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 , about 200
  • irinotecan is administered intravenously.
  • irinotecan is administered intravenously to a subject at a dose ranging from about 50 mg/m 2 to about 150 mg/m 2 .
  • irinotecan is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m 2 to about 150 mg/m 2 .
  • irinotecan is administered intravenously to a subject once per day for five consecutive days at a dose ranging from about 50 mg/m 2 to about 150 mg/m 2 on days 1-5, then again intravenously once per day for five consecutive days on days 28-32 at a dose ranging from about 50 mg/m 2 to about 150 mg/m 2 , then again intravenously once per day for five consecutive days on days 55-59 at a dose ranging from about 50 mg/m 2 to about 150 mg/m 2 .
  • the invention provides administration of an effective amount of: (i) a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) one or more other anticancer agents.
  • a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) one or more other anticancer agents are administered in doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) one or more other anticancer agents act synergistically and are administered in doses that are less than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • the dosage of the (i) Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound and (ii) one or more other anticancer agents administered as well as the dosing schedule can depend on various parameters, including, but not limited to, the cancer being treated, the patient's general health, and the administering physician's discretion.
  • the other anticancer agent is O-6-benzylguanine.
  • the other anticancer agent is O-6-benzylguanine and temozolomide.
  • the other anticancer agent is O-6-benzylguanine and procarbazine.
  • the other anticancer agent is O-6-benzylguanine and dacarbazine.
  • Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be administered to a subject that has undergone or is currently undergoing one or more additional anticancer therapies including, but not limited to, surgery, radiation therapy, or immunotherapy, such as cancer vaccines.
  • the invention provides methods for treating or preventing cancer comprising administering to a subject in need thereof (a) an amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound effective to treat or prevent cancer; and (b) another anticancer therapy including, but not limited to, surgery, radiation therapy, or immunotherapy, such as a cancer vaccine.
  • the other anticancer therapy is radiation therapy.
  • the other anticancer therapy is surgery.
  • the other anticancer therapy is immunotherapy.
  • the present methods for treating or preventing cancer comprise administering (i) an effective amount of a Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound and (ii) radiation therapy.
  • the radiation therapy can be administered concurrently with, prior to, or subsequent to the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound, in one embodiment at least an hour, five hours, 12 hours, a day, a week, a month, in another embodiment several months (e.g., up to three months), prior or subsequent to administration of the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compounds.
  • any radiation therapy protocol can be used depending upon the type of cancer to be treated.
  • X-ray radiation can be administered; in particular, high-energy megavoltage (radiation of greater that 1 MeV energy) can be used for deep tumors, and electron beam and orthovoltage X-ray radiation can be used for skin cancers.
  • Gamma-ray emitting radioisotopes such as radioactive isotopes of radium, cobalt and other elements, can also be administered.
  • the invention provides methods of treatment of cancer using a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy results in negative side effects in the subject being treated.
  • the subject being treated can, optionally, be treated with another anticancer therapy such as surgery, radiation therapy, or immunotherapy.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can also be used in vitro or ex vivo, such as for the treatment of certain cancers, including, but not limited to leukemias and lymphomas, such treatment involving autologous stem cell transplants.
  • This can involve a process in which the subject's autologous hematopoietic stem cells are harvested and purged of all cancer cells, the subject's remaining bone-marrow cell population is then eradicated via the administration of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and/or radiation, and the resultant stem cells are infused back into the subject. Supportive care can be subsequently provided while bone marrow function is restored and the subject recovers.
  • the Tetracyclic Amino Compounds and the Tetracyclic Carboxamido Compounds are advantageously useful in veterinary and human medicine. As described above, The Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds are useful for treating or preventing a Condition in a subject in need thereof.
  • Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be administered in amounts that are effective to treat or prevent a Condition in a subject.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be administered as a component of a composition that comprises a physiologically acceptable carrier or vehicle.
  • the present compositions, which comprise a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound can be administered orally.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa) and can be administered together with another biologically active agent. Administration can be systemic or local.
  • Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, and can be administered.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin.
  • administration will result in the release of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound into the bloodstream.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds are administered orally.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be desirable to administer the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds locally.
  • This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be desirable to introduce the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds into the central nervous system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural injection, and enema.
  • Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler of nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon oar, synthetic pulmonary surfactant.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
  • Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Treat or prevent et al., Liposomes in Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)).
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • Other controlled or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used.
  • a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng . 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J.
  • polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem . 2:61 (1983); Levy et al., Science 228:190. (1935); During et al., Ann. Neural . 25:351 (1989); and Howard et al., J. Neurosurg . 71:105 (1989)).
  • a controlled- or sustained-release system can be placed in proximity of a target of the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds, e.g., the spinal column, brain, skin, lung, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.
  • compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the subject.
  • Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipients can be saline, gum acacia; gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a particularly useful excipient when the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
  • suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills; pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions. aerosols, sprays, suspensions, or any other form suitable for use.
  • the composition is in the form of a capsule (see e.g. U.S. Pat. No. 5,698,155).
  • suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.
  • compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs for example.
  • Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound are also suitable for orally administered compositions.
  • fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time-delay material such as glycerol monostearate or glycerol stearate can also be used.
  • Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment the excipients are of pharmaceutical grade.
  • compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection.
  • a local anesthetic such as lignocaine to lessen pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized-powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
  • Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • Tetracyclic Amino Compounds and the Tetracyclic Carboxamido Compounds can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but arc not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354;556; and 5,733,556, each of which is incorporated herein by reference.
  • Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.
  • a controlled- or sustained-release composition comprises a minimal amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound to treat or prevent the Condition in a minimal amount of time.
  • Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased subject compliance.
  • controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound, and can thus reduce the occurrence of adverse side effects.
  • Controlled- or sustained-release compositions can initially release an amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound can be released from the dosage form at a rate that will replace the amount of Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound being metabolized and excreted from the body.
  • Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.
  • the amount of the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound that is effective in the treatment or prevention of a Condition can be determined by standard clinical techniques.
  • in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of the practitioner and each subject's circumstances in view of, e.g., published clinical studies.
  • Suitable effective dosage amounts range from about 10 micrograms to about 5 grams about every 4 h, although they are typically about 500 mg or less per every 4 hours.
  • the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours.
  • Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months.
  • the effective dosage amounts described herein refer to total amounts administered; that is, if more than one Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound is administered, the effective dosage amounts correspond to the total amount administered.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99%; and in another embodiment from about 1% to about 70% of the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound by weight or volume.
  • the dosage regimen utilizing the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; and the particular Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound employed.
  • a person skilled in the art can readily determine the effective amount of the drug useful for treating or preventing the Condition.
  • the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, the Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen.
  • Topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound ranges from about 0.1% to about 15%, w/w or w/v.
  • the compositions comprise an amount of (i) a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) the other anticancer agent which together are effective to treat or prevent cancer.
  • the amount of (i) a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) the other anticancer agent is at least about 0.01% of the combined combination chemotherapy agents by weight of the composition. When intended for oral administration, this amount can be varied from about 0.1% to about 80% by weight of the composition.
  • compositions can comprise from about 4% to about 50% of combined amount of (i) a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and (ii) the other anticancer agent by weight of the composition.
  • Other compositions of the present invention are prepared so that a parenteral dosage unit contains from about 0.01% to about 2% by weight of the composition.
  • Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
  • Animal model systems can be used to demonstrate safety and efficacy.
  • the present methods for treating or preventing a Condition in a subject in need thereof can further comprise administering another prophylactic or therapeutic agent to the subject being administered a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound.
  • the other prophylactic or therapeutic agent is administered in an effective amount.
  • the other prophylactic or therapeutic agent includes, but is not limited to, an anti-inflammatory agent, an anti-renal failure agent, an anti-diabetic agent, and anti-cardiovascular disease agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anxiolytic agent, and an analgesic agent.
  • the other prophylactic or therapeutic agent is an agent useful for reducing any potential side effect of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound.
  • potential side effects include, but are not limited to, nausea, vomiting, headache, low white blood cell count, low red blood cell count, low platelet count, headache, fever, lethargy, muscle aches, general pain, bone pain, pain at an injection site, diarrhea, neuropathy, pruritis, mouth sores, alopecia, anxiety or depression.
  • the Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound can be administered prior to, concurrently with, or after an anti-inflammatory agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound can be administered prior to, concurrently with, or after an anti-renal failure agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound can be administered prior to, concurrently with, or after an anti-diabetic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound can be administered prior to, concurrently with, or after an anti-cardiovascular disease agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound can be administered prior to, concurrently with, or after an antiemetic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound can be administered prior to, concurrently with, or after a hematopoietic colony stimulating factor, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks or 4 weeks of each other.
  • the Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound can be administered prior to, concurrently with, or after an opioid or non-opioid analgesic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound can be administered prior to, concurrently with, or after an anxiolytic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • Effective amounts of the other prophylactic or therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other prophylactic or therapeutic agent's optimal effective amount range. In one embodiment of the invention, where another prophylactic or therapeutic agent is administered to a subject, the effective amount of the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound is less than its effective amount would be where the other prophylactic or therapeutic agent is not administered. In this case, without being bound by theory, it is believed that The Tetracyclic Amino Compounds or the Tetracyclic Carboxamido Compounds and the other prophylactic or therapeutic agent act synergistically to treat or prevent a Condition.
  • Anti-inflammatory agents useful in the methods of the present invention include but are not limited to adrenocorticosteroids, such as cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6 ⁇ -methylprednisolone, triamcinolone, betamethasone, and dexamethasone; and non-steroidal anti-inflammatory agents (NSAIDs), such as aspirin, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone, rofecoxib, celecoxib, etodolac, and nimesulide.
  • NSAIDs non
  • Anti-renal failure agents useful in the methods of the present invention include include but are not limited to ACE (angiotensin-converting enzyme) inhibitors, such as captopril, enalaprilat, lisinopril, benazepril, fosinopril, trandolapril, quinapril, and ramipril; diuretics, such as mannitol, glycerin, furosemide, toresemide, tripamide, chlorothiazide, methyclothiazide, indapamide, amiloride, and spironolactone; and fibric acid agents, such as clofibrate, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate.
  • ACE angiotensin-converting enzyme
  • Anti-diabetic agents useful in the methods of the present invention include include but are not limited to glucagons; somatostatin; diazoxide; sulfonylureas, such as tolbutamide, acetohexamide, tolazamide, chloropropamide, glybenclamide, glipizide, gliclazide, and glimepiride; insulin secretagogues, such as repaglinide, and nateglinide; biguanides, such as metformin and phenformin; thiazolidinediones, such as pioglitazone, rosiglitazone, and troglitazone; and ⁇ -glucosidase inhibitors, such as acarbose and miglitol.
  • Anti-cardiovascular disease agents useful in the methods of the present invention include include but are not limited to carnitine; thiamine; and muscarinic receptor antagonists, such as atropine, scopolamine, homatropine, tropicamide, pirenzipine, ipratropium, tiotropium, and tolterodine.
  • Antiemetic agents useful in the methods of the present invention include include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.
  • Hematopoietic colony stimulating factors useful in the methods of the present invention include, but are not limited to, filgrastim, sargramostim, molgramostim and epoietin alfa.
  • Opioid analgesic agents useful in the methods of the present invention include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine, methadone, isomethadone and propoxyphene.
  • morphine heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine
  • Non-opioid analgesic agents useful in the methods of the present invention include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac.
  • Anxiolytic agents useful in the methods of the present invention include, but are not limited to, buspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam, chlorazepate, clonazepam, chlordiazepoxide and alprazolam.
  • kits that can simplify the administration of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound to a subject.
  • a typical kit of the invention comprises a unit dosage form of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound.
  • the unit dosage form is a container, which can be sterile, containing an effective amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and a physiologically acceptable carrier or vehicle.
  • the kit can further comprise a label or printed instructions instructing the use of the Tetracyclic Amino Compound or the Tetracyclic Carboxamido Compound to treat or prevent a Condition.
  • the kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of the other prophylactic or therapeutic agent.
  • the kit comprises a container containing an effective amount of a Tetracyclic Amino Compound or a Tetracyclic Carboxamido Compound and an effective amount of another prophylactic or therapeutic agent.
  • examples of other prophylactic or therapeutic agents include, but are not limited to, those listed above.
  • Kits of the invention can further comprise a device that is useful for administering the unit dosage forms.
  • a device that is useful for administering the unit dosage forms. Examples of such a device include, but are not limited to, a syringe, a drip bag, a patch, an inhaler, and an enema bag.
  • Raw murine macrophages were treated with an illustrative Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound for 15 minutes prior to the addition of peroxynitrite (750 ⁇ M) for a further 15 minutes.
  • the media were removed and replaced with 0.5 ml HEPES (pH 7.5) containing 0.01% digitonin and 3 H-NAD (0.5 ⁇ Ci ml ⁇ 1 , final concentration of NAD + in buffer is 20 nM/L) for 20 minutes.
  • the cells were then scraped from the wells and placed in Eppendorf tubes containing 200 ⁇ l of 50% (w/v) ice-cold trichloroacetic acid (TCA).
  • the tubes were then placed at 4° C. After 4 hr the tubes were centrifuged at 1800 g for 10 minutes and the supernatant removed. The pellets were washed twice with 500 ⁇ l ice-cold 5% TCA. The pellets were solubilized in 250 ⁇ l NaOH (0.1 M) containing 2% SDS overnight at 37° C. and the PARS activity was then determined by measuring the radioactivity incorporated using a Wallac scintillation counter. The solubilized protein (250 ⁇ l) was mixed with 5 ml of scintillant (ScintiSafe Plus, Fisher Scientific) before being counted for 10 minutes. The EC 50 value was calculated from a dose-response curve.
  • an illustrative Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound can be tested for its ability to prevent the oxidant-induced suppression of the viability of the cells and as such, this assay represents an in vitro model of reperfusion related cell death in ischemic organs.
  • the effect of an illustrative Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound can be determined usng a systemic inflammatory model induced by bacterial lipopolysaccharide (LPS), which is reported to be responsible for causing reperfusion injurys and inflammatory diseases such as septic shock and systemic inflammatory response syndrome in animals (see Parrillo, N. Engl. J. Med ., 328:1471-1478 (1993) and Lamping, J. Clin. Invest . 101:2065-2071 (1998).
  • LPS bacterial lipopolysaccharide
  • the efficacy of an illustrative Tetracyclic Amino Compound or Tetracyclic Carboxamido Compound in a mouse model of ischemic and reperfused gut can be determined according to the method described in Liaudet et al., Shock 2000, 14(2):134-41.
  • PARS inhibitors and PARS deficiency are known to reduce the development of diabetes and the incidence of diabetic complications.
  • a single high-dose streptozotocin model of diabetes can be used as conducted as described in Mabley et al., Br J Pharmacol . 2001, 133(6):909-9; and Soriano et al., Nat Med . 2001, 7(1):108-13.

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